Purpose: The goal of this phase I study is to evaluate whether the combination of 5-FU and eniluracil can be given safely to patients with locally advanced or unresectable upper-GI malignancies (primarily pancreatic cancer); to determine whether the drug levels achieved are similar to those of continuous infusion 5-FU; and to determine whether this combination has any preliminary evidence of activity in this disease. The study will determine the maximal tolerated dose and recommended phase II dose of 5-FU plus eniluracil. It will describe non-dose-limiting toxicities associated with the use of radiation, 5-FU and eniluricil; determine if the pharmacokinetics of oral 5- FU or eniluricil are altered by concomitant upper GI radiation; and preliminarily describe the radiographic response rate, the surgical resectability rate, overall and disease free survival associated with the use of this combined modality regimen. Methods: Patients are being treated with radiation therapy (total 5040 cGy) concomitantly with chemotherapy over approximately five weeks. The initial dose level of chemotherapy is 0.5 mg/m2 /day 5-FU and 5 mg/m2 /day eniluracil, given every 12 hours by mouth. Twelve blood samples for assay of study drugs and uracil plasma concentrations are drawn over 12 hours on treatment days 8 and 31. Also on days 8 and 31, urine is collected for 12 hours. Results: Three patients were treated on this study during the reporting period. There have been no reportable adverse events. Significance: The combination of medications used in this study may in later studies be proven to be more efficacious and easier to administer than current therapy. Future plans: The study is ongoing.